The work proposed is focused on MSG, which is a group of variable surface antigens of the pathogenic fungus, P. carinii. Surface antigens such as MSG are of fundamental interest because they function at the host-pathogen interface. The importance of this interface to pathogenic microbes is illustrated by the complex genetic systems used by certain protozoa and bacteria to generate diversity on their surface. P. carinii MSG genes appear to endow this fungus with a similar capacity to vary its surface. The broad, long-term objectives of the research proposed are to characterize antigenic variation in P. carinii, to understand the genetic mechanism that controls it, and to study the relationship between antigenic variation and host-pathogen interactions. The experiments focus primarily on rat P. carinii because it is tractable. Studies on human P. carinii are also proposed. Hypotheses to be tested include (i) P. carinii use DNA recombination to change the MSG gene that is attached to a unique expression site. (ii) Changing this gene leads to a change in the MSG on the cell surface. (iii) P. carinii that infects humans has an MSG expression system similar to that in P.carinii that infects rats. The proposed research has the following four Specific Aims: 1. Determine the genetic basis for antigenic variation. 2. Analyze the dynamics and nature of MSG variation in the inoculated rat model. 3: Determine if the host immune response influences the frequency or nature of antigenic variation. 4. Analyze the MSG system in human P. carinii. These Aims will be addressed using rats that are naturally infected, and rats that have been inoculated with a low dose of P. carinii. Human P. carinii will be obtained from patients. Molecular genetic and immunohistochemical tools will be used to study expression of MSG genes and proteins.